Substituted amides of tertiary butyl acetic acid



Patented Nov. 10, 1936 UNITED STATES PATENT OFFICE SUBSTITUTED AMIDES OF TERTIARY BUTYL ACETIC ACID Frank C. Whitmore, State College, Pa., and August H. Homeyer, St. Louis, Mo., assignors to Mallinckrodt Chemical Works, St. Louis, Mo., a corporation of Missouri No Drawing. Application November 3, 1934, Serial No. 751,418

6 Claims.

wherein X represents hydrogen or a halogen; R represents hydrogen or a hydrocarbon radical; and R" represents a hydrocarbon radical.

This application is in part a continuation of our application, Serial No. 666,512, filed April 1'7, 1933, and entitled Acyl halides of tertiary butyl acetic acid, now Patent No. 2,034,850, dated March 24, 1936.

Among the several objects of the invention may be noted the provision of a series of substituted amides of tertiary butyl acetic acid corresponding to the above type formula which all embody the therapeutic effect of the presence of the quaternary carbon atom. Other objects will be in part obvious and in part pointed out hereinafter.

The invention accordingly comprises the elements and combinations of elements, and features of composition, which will be exemplified in the substances hereinafter described, and the scope of the application of which will be indicated in the following claims.

It has recently been determined that certain organic products including as a constituent thereof a quaternary carbon atom (that is, a carbon atom to which are directly linked four other carbon atoms) have valuable therapeutic properties, particularly in the field of hypnotics, sedatives, soporifics, analgesics, and bactericides and the like.

Among the products so constituted, the substituted amides of tertiary butyl acetic acid are a most valuable group. These amides have been determined to have valuable hypnotic or sedative or soporific effects when administered therapeutically, such effects being markedly improved over similar effects obtained from the analogous compounds (such as the substituted amides of secondary butyl acetic acid) not containing the quaternary carbon atom. The enhanced effect seems to be due to the fact that the quaternary carbon atom represents the maximum degree of branching in the structure of the compound.

Likewise, the substituted amides falling within the type formula above seem to possess enhanced therapeutic effects over. the unsubstituted amide of the same acid.

The substances set forth as examples hereinafter fall into two generic classes (referring to the type formula above), namely: substances wherein X in the type formula is a hydrogen, and substances wherein X is a halogen, specifically, bromine. The first class of substances are pre- 5' pared by reacting the appropriate amine with tertiary butyl acetyl chloride, according to the type reaction:

The second class of substances are prepared by reacting the appropriate amine with alpha-bromo tertiary butyl acetyl chloride, according to the type reaction:

Both tertiary butyl acetyl chloride and alphabromo tertiary butyl acetyl chloride are obtained in pure form according to our said copending application, Serial No. 666,512.

Example 1.-The monomethyl-amide of tertiary butyl acetic acid This substance, (CH3)3CCH2--CONH-CH3, is prepared by reacting monomethyl amine, which is commercially obtainable, with tertiary butyl acetyl chloride. It is typical of substances corresponding to the type formula wherein X is hydrogen, R is hydrogen, and R is an alkyl.

Example 2.The monoethyl-amide of the tertiary butyl acetic acid This substance,

(CH3) 3C-CH2CONHCH2CH3,

is prepared'by reacting monoethyl amine, which is commercially obtainable, with tertiary butyl 40 acetyl chloride. Like Example 1, it is typical of substances corresponding to the type formula wherein X is hydrogen, R, is hydrogen, and R" is an alkyl.

is prepared by reacting monoamyl amine, which is commercially obtainable, with tertiary butyl acetyl chloride. Like Examples 1 and 2, it is typical of substances corresponding to the type formula wherein X is hydrogen, R is hydrogen, and R" is an alkyl.

Example 4.-The monoallyl-amide of tertiary butyl acetic acid This substance,

(CH3) 3C-CH2CONH--CH2CH=CH2,

is prepared by reacting monoallyl amine, which is commercially obtainable, with tertiary butyl acetyl chloride. It is typical of substances within the type formula wherein X is hydrogen, R is hydrogen, and R" is an alkylene.

Example 5.-The monocyclohexyl-amide of tertiary butyl acetic acid This substance,

(CH3) 3CCH2--CONH-C6H11,

is prepared by reacting mono-cyclohexyl amine, which is commercially obtainable, with tertiary butyl acetyl chloride. It is typical of substances within the type formula wherein X is hydrogen, R. is hydrogen, and R is a cycloalkyl.

Example 6.-The mono-2,2-dimethylpropyl-amide of tertiary butyl acetic acid This substance,

(CI-I3) 3C-CH2CONH-CH2C (CH3) 2CH3,

Example 7.-The anilide of tertiary butyl acetic acid This substance,

(CI-I3) 3C-CH2--CONH-C6H5,

is prepared by reacting aniline with tertiary butyl acetyl chloride. It is typical of substances within the type formula wherein X is hydrogen, R is hydrogen, and R is an aryl.

The crude salt, which is in the form of yellow crystals, may be purified by boiling its alcoholic solution with bone char and crystallized on diluting with water.

Example 8.-The dimethyl-amide of tertiary butyl acetic acid This substance,

is prepared by reacting dimethyl amine, commercially obtainable, with tertiary butyl acetyl chloride. It is typical of substances within the type formula wherein X is hydrogen, R is an alkyl, and R. is also an alkyl.

diethyl-amide of tertiary butyl Example 9.-The

' acetic acid This substance,

(CH3) 3CCH2-CON-(CH2CH3) 2,

is prepared by reacting diethyl amine with tertiary butyl acetyl chloride. It is typical, along with Example 8, of substances within the type formula wherein X is hydrogen, and R and R are both alkyls.

As exemplary of this entire series of derivatives, specific instructions are here given for the preparation of this substance: grams of diethyl amine are dissolved in 200 cc. of ethyl ether cooled in ice. 21 grams of tertiary butyl acetyl chloride are then added slowly from a separatory funnel, with shaking. A vigorous reaction occurs, with the evolution of heat and the precipitation of the diethyl amine hydrochloride. The solid is filtered off and extracted with ether to obtain the residue of the amide. The ether solutions are then combined and evaporated. The resulting oil is then fractionated, at 3 mm. pressure, to obtain the product.

Example 10.The methylphenyl-amide of tertiary butyl acetic acid This substance,

(CH3) 3CCH2-CON (CH3) (CeHs) is prepared by reacting methylphenyl amine (monomethyl aniline), commercially obtainable, with tertiary butyl acetyl chloride. It is typical of substances within the type formula wherein X is hydrogen, R, is an alkyl, and R. is an aryl.

If in all of the above ten examples, alpha-bromo tertiary butyl acetyl chloride is substituted for the tertiary butyl acetyl chloride, then a corresponding series of derivatives is obtained in which, referring to the type formula, X is bromine, while R. and B. have in each case the same indication as in the respective examples. The following is a tabulation of such substances, the name and formula of each being given:

Example 11.--(From Example 1) The monomethyl-amide of alpha-bromo tertiary butyl acetic acid (CH3) 3C-CHBl-CONHCH3.

Example 12.-(From Example 2) The monoethyl-amide of alpha-bromo tertiary butyl acetic acid (CH3) 3CCHBr-CONHCH2CH3.

Example 13.-(From Example 3). The monoamyl-amide of alpha-bromo tertiary butyl acetic d acid (CH3) 3CCHBl'-CONH-(CH2) 4CH3.

Example 14.(From Example 4). The monoallyl-amide of alpha-bromo tertiary butyl acetic Example 15.(From Example 5). The monocyclohexyl-amide of alpha-bromo tertiary butyl acetic acid (CH3) 3CCHBrCONHCcH11.

Example 16.-(From Example 6). The mono- 2,2-dimethylpropyl-amide of alpha-bromo tertiary butyl acetic acid Example 17.(From Example '7). The anilide of alpha-bromo tertiary butyl acetic acid Example 20.-(From Example 10.) The methylphenyl amide of alpha-bromo tertiary butyl acetic acid (CH3)aC-CHBrCON(CH3) (CsHs) The following table gives some of the physical properties of the exemplary substances heretofore set forth:

We claim: 1. A substituted amide of tertiary butyl acetic acid corresponding to the type formula:

Substituents in type formula (CH )3CCHX-CONR'R" Example No. M. P B. P. (mm.) Form 11% X a R" CH3 93 (5 mm) Oil -CH2-CH3 98 (6 mm Oil 1. 4422 (CH2)4-CH3 130 (7 mm Oil 1. 4481 -CHz-CH=CH3 105 (7 mm Oil 1. 4575 C|;Hu Oryst --CHzC(CHa)g-CH -CaH5 CH3 1. 4450 -CHz-CH3 1. 4440 CBH5 1. 4980 -CH3 CH2CH3 (CH2)4CH3 1. 4830 CH2-CH=OH2 1. 4989 C5Hu CH2-C(CH3)2CH:4 1667 Oryst eHs lane-2y; Cryst -CH3 95 (5 mm Oil 1. 4930 -CH2CH3 35-6 IDS-9 (5 mm.) Cryst. M -Br a COH5 140 (6 mm.) Oil 1.4990

In the above table, M. P. indicates melting point; B. P. (mm.) indicates boiling point under so many millimeters of mercury pressure; and

indicates the index of refraction, at 20, with respect to the sodium-D line. Degrees temperature are given to the centigrade scale throughout this application.

Numerous other substituted amides falling within the type formula can be made by analogous methods.

Other methods of preparation may likewise be used for obtaining the substances hereinbefore mentioned. For example, the acid chlorides used throughout may be replaced by acid bromides.

In view of the above, it will be seen that the several objects of the invention have been achieved and other advantageous results attained.

As many changes could be made in carrying out the above syntheses and in eifecting the above compositions without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

where X represents hydrogen or a halogen, R represents hydrogen or a hydrocarbon radical, and R" represents a hydrocarbon radical.

2. A substituted amide of tertiary butyl acetic acid corresponding to the type formula:

(CH3) aC-CHz-CONRR' where R represents hydrogen or a hydrocarbon radical, and R represents an alkyl, alkylene, cycloalkyl, or aryl.

3. A substituted amide of alpha-bromo tertiary butyl acetic acid corresponding to the type formula:

where R represents hydrogen or a hydrocarbon radical, and R represents an alkyl, alkylene, cycloalkyl, or aryl.

4. The anilide of tertiary butyl acetic acid. 5. The diethyl-amide of tertiary butyl acetic acid.

6. The diethyl-amide of alpha-bromo tertiary butyl acetic acid.

FRANK C. WHITMORE. AUGUST H. I-IOMEYER. 

